Vertex Pharmaceuticals Incorporated has been grabbing headlines recently related to its revolutionary cystic fibrosis drug Kalydeco (ivacaftor), which is currently approved for people with CF aged 6 and older who have at least one copy of the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Kalydeco functions as a CFTR potentiator, and is viable treatment for some ten percent of cystic fibrosis patients, and while it is considered an effective, even transformational, therapeutic agent for that cohort, albeit at extremely high prices due to limited economies of scale, a broader objective for Vertex is to pair Kalydeco with other CFTR correctors in hope of making it effective in treating a larger proportion of or the entire CF patient population.

Cystic Fibrosis (CF) is a rare but devastating genetic disease for which there is currently no cure. It is caused by defective or missing CFTR proteins at the cell surface that result from mutations in the CFTR gene. The defective function or absence of CFTR proteins in people with CF results in poor flow of salt and water into and out of the cell in a number of organs, including the lungs. In people with two copies of the F508del mutation, the CFTR protein is not processed, or folded, normally within the cell and generally does not reach the cell surface.

Vertex’s developmental drug Lumacaftor is designed to address the processing defect of F508del-CFTR — the defective protein that causes the disease due to the amino acid phenylalanine being missing in position 508 — to enable it to reach the cell surface where ivacaftor can further enhance the protein’s function. In North America, Europe, and Australia, there are more than 22,000 people ages 12 and older who have two copies of the F508del mutation. The defect is found in about 60% of cystic fibrosis patients in Europe, and in about 90% of persons with some mutation in the CFTR gene. It is also estimated that more than 7,000 people with CF, including those with the G551D mutation, have CFTR mutations that may respond to ivacaftor treatment.

As a CFTR corrector, Vertex hopes that Lumacaftor can compliment each other, with the latter augmenting Kalydeco to expand its efficacy, a hypothesis that’s been tested in Phase 3 studies, dubbed the TRAFFIC and TRANSPORT, for CF patients with the F508del mutation, representative of about 50% of the CF patient population. Consequently, if the Lumacaftor/Kalydeco pairing worked well, it could constitute a true breakthrough treatment option for cystic fibrosis.

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“KALYDECO was the first medicine to treat the underlying cause of CF, and we believe that KALYDECO is just the first step of our work in CF,” says Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. “Our goal in CF is to help many more people with this disease and to evaluate multiple combinations of CFTR modulators aimed at providing further benefit for people with CF.” Vertex’s combination of lumacaftor and ivacaftor is the first regimen designed to treat the underlying cause of CF in people with two copies of the F508del mutation.

In addition to the primary endpoint analysis for each study, a pre-specified pooled analysis evaluated the two combination treatment groups by dose from each study (two dose arms of lumacaftor 600 mg once daily in combination with ivacaftor 250 mg q12h combined; two dose arms of lumacaftor 400 mg q12h in combination with ivacaftor 250 mg q12h combined; two placebo arms combined), and 1,108 people enrolled and received at least one dose of study drug in the two studies (549 in TRAFFIC; 559 in TRANSPORT) at approximately 200 clinical trial sites throughout North America, Europe and Australia.

All four treatment arms within the studies met their primary endpoint. Additionally, statistically significant mean absolute and relative improvements in lung function were observed for all four treatment groups, both within group and versus placebo, at all time points within the study (Weeks 2, 4, 8, 16 and 24). As patients in the study continued to be treated with their standard CF medicines, improvements observed for patients in the combination treatment arms were in addition to any benefits experienced with the use of other CF medicines. The mean baseline lung function of patients was approximately 61 percent predicted FEV1 for patients who received the combination regimen and for patients who received placebo.

Kalydeco / Lumacaftor Combination Shown Effective In Latest Studies

Vertex today announced results from the two Phase 3 studies of lumacaftor in combination with ivacaftor showing statistically significant improvements in lung function in people ages 12 and older with CF who have two copies (homozygous) of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. All four 24-week combination treatment arms in the TRAFFIC and TRANSPORT studies met their primary endpoint of mean absolute improvement in ppFEV1 from baseline compared to placebo at the end of treatment. Mean absolute improvements in ppFEV1 of between 2.6 and 4.0 percentage points from baseline compared to placebo were observed across the studies (p≤0.0004), with mean relative improvements of 4.3 percent to 6.7 percent (p≤0.0007). Pooled analysis of Phase 3 studies showed statistically significant reductions of 30 and 39 percent in rate of pulmonary exacerbations for those who received the combination regimens compared to those who received placebo. There were also statistically significant improvements in body mass index compared to placebo and in the proportion of patients with a 5 percent or greater relative improvement in ppFEV1 compared to placebo.

Vertex reports that the combination regimens were generally well tolerated, with the most common adverse events, regardless of treatment group, being infective pulmonary exacerbation, cough, headache and increased sputum, resulting in 4.2 percent of patients who received the combination regimens discontinuing treatment because of adverse events compared to 1.6 percent of those who received placebo. Across the two studies, elevated liver enzymes (greater than three times the upper limit of normal) were observed in 5.2 percent of patients who received combination therapy compared to 5.1 percent of those who received placebo. Seven patients who received combination therapy experienced serious adverse events related to abnormal liver function tests, compared to zero patients who received placebo. Following discontinuation or interruption of the combination treatment, liver function tests returned to baseline for six of the seven patients and the seventh patient’s liver function tests improved substantially. All patients who completed the 24-week study, regardless of treatment assignment, were given the opportunity to enroll in a rollover study. Following the end of the 24-week dosing period, more than 1,000 patients chose to enter the rollover study to receive a combination regimen.

A Vertex release notes that data from a pre-specified pooled analysis showed improvements in multiple key secondary endpoints. For patients who received the combination regimens compared to those who received placebo, there were statistically significant reductions in the rates of pulmonary exacerbations and statistically significant improvements in both body mass index and the proportion of patients with at least a 5 percent relative improvement in ppFEV1. Statistically significant changes were not consistently observed for patient-reported respiratory symptoms as reported in the CF questionnaire-revised (CFQ-R).

Based on the data from the two studies, Vertex plans to submit regulatory applications for approval in multiple countries, including a New Drug Application (NDA) in the United States and Marketing Authorization Application (MAA) in Europe, in the fourth quarter of 2014 for people with CF ages 12 and older who have two copies of the F508del mutation.

“On average, people with CF who have two copies of the F508del mutation lose nearly two percent of their lung function each year, underscoring the urgent need for new medicines that address the underlying cause of this disease,” says Bonnie Ramsey, M.D., Professor of Pediatrics, University of Washington School of Medicine, Director of the Center for Clinical and Translational Research at Seattle Children’s Research Institute and a lead Principal Investigator for the TRANSPORT study. “These data showed consistent evidence of clinical benefit in lung function and other measures of the disease. The significant improvements in pulmonary exacerbations are particularly important given the potential for these events to result in hospitalizations, permanent lung damage and the need for additional treatment with antibiotics and other medicines.”

“The combination of lumacaftor and ivacaftor is the first regimen designed to address the underlying cause of CF for people with the most common form of the disease, and based on these data, we plan to move as fast as possible to submit applications for approval of this combination regimen in countries around the world,” comments Jeffrey Chodakewitz, M.D., Senior Vice President and Chief Medical Officer at Vertex. “I would like to thank the more than 1,100 people who took part in these studies worldwide, as well as their families, friends and caregivers.”

“These data mark an exciting day for the CF community and validate our more than 30-year commitment to develop medicines that target the underlying basic defect of cystic fibrosis for all people with this devastating disease,” affirms Robert J. Beall, Ph.D., President and CEO, Cystic Fibrosis Foundation. “While we await the FDA’s review of these data, we’re grateful to the many people with CF, families and volunteers who have committed their time and resources to help accelerate our efforts to bring effective therapies to all people living with the disease.”

Vertex says it recognizes that there are people with CF who have very severe disease and who are in immediate need of new CF medicines. Based on the data from these studies, Vertex will work with the CF community, doctors and regulators to explore options to make the combination of lumacaftor and ivacaftor available to certain patients who have two copies of the F508del mutation while we are seeking approval of this regimen from regulatory agencies around the world.

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Vertex initiated its CF research program in 1998 as part of a collaboration with CFFT, the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. This collaboration was expanded to support the accelerated discovery and development of Vertex’s CFTR modulators.

Vertex hosted a conference call and webcast today at 8:00 a.m. ET to discuss the TRAFFIC and TRANSPORT results, and it will be available on the company’s website until July 24, 2014 at http://www.vrtx.com in the “Investors” section under “Events and Presentations.”

Disclaimer:

Cystic Fibrosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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